Cisplatin (cis-diamminedichloroplatinum, abbreviated as CDDP) is a metal complex having anti-cancer activity, which is discovered by B. Rosenborg et al. in 1965 for the first time. CDDP has the characteristics such as a wide anti-cancer spectrum, a strong effect, a synergism effect with various antineoplastic drugs, and no cross resistance. Therefore, CDDP is one of the most common drug used in the combination chemotherapy. Currently, CDDP has good effect for treating genital system tumor, malignant lymphoma, cancer in head and neck, bladder carcinoma, lung cancer, and the like. CDDP is invalid in oral administration. The clinical applying method is generally the administration in a manner of intravenous drip. After the intravenous injection, CDDP rapidly disappears from the blood plasma, and rapidly distributes all over the body, especially, mostly distributes in liver, kidney, large and small intestine and skin, therefore the toxic side effect is large. For example, it may cause renal toxicity, bone marrow depression and gastrointestinal tract side effect, and the like. Meanwhile, the half life of CDDP in blood is short, therefore the ratio of it arriving at the focus is very low, and the drug efficiency is low.
In order to prolong the half life of the drug in blood, reduce the nonspecific adsorption effect between the drug and proteins so as to improve the drug efficiency, a general method is to use a polymer material as the carrier for delivering the drug. Recently, micrometer and nanometer sized polymer carriers are rapidly developed, such as micelles, vesicles and nano particles. These types of polymer carriers may effectively distribute the drug molecules therein, and by using various response manners of the carriers, the delivery and controlled release of the drug is achieved. The internal environment of the tumor cell generally appears as “three high factors and one low factor”, i.e., a low oxygen level, a low sugar level, and a low pH value, and a high glutathione concentration, wherein the low pH value is especially prominent. The pH value of endosome and lysosome in advanced stage may be as low as 5.0 (Advanced Functional Materials, 19(22): 3580˜3589). In addition, the tumor tissue has the characteristics of abundant blood vessels, a relatively broad vascular wall gap, a poor structural integrity, lose of lymphatic return, and the like, such that a high molecule substance and lipid granule have high permeability and retention. Therefore, nanometer to micrometer sized drug carrier systems have substantively “improved effect of penetration and retention”, that is, EPR effect. Using the passive targeting manner of EPR effect, the drug can be effectively concentrated in the tumor tissue, meanwhile the toxic and side effect on the non-focus portion can be decreased.
It is disclosed in the prior art various methods of developing CDDP formulation using a polymer carrier for carrying the drug. For example, Kataoka et al. uses CDDP complexed with polyethylene glycol-b-polyglutamic acid to prepare micelles (NC-6004), which drug enters II stage of the clinical test. However, the obtained micelles are formed by the crosslinking effect between the polyamino acid side chains, so that lyophilized powder obtained after lyophilizing the complex obtained by the method is difficult to be redissolved. Stenzel et al. introduces mercapto acetic acid and mercapto succinic acid into the side chain of the polymer using a “mercapto-alkynyl” and “mercapto-alkenyl” Click reaction, obtaining a CDDP complex (Biomacromolecules 12(5): 1738-1751). This complex has good dissolvability. However, the biocompatibility of the polymer used as the carrier is poor, which cannot be degraded. Therefore, the further use thereof is limited.